Human Monoclonal Antibodies for Encephalitic Alphaviruses

脑炎甲病毒的人单克隆抗体

基本信息

批准号：
10539155
负责人：
James E Crowe
金额：
$ 85.81万
依托单位：
VANDERBILT UNIVERSITY MEDICAL CENTER
依托单位国家：
美国
项目类别：
财政年份：
2022
资助国家：
美国
起止时间：
2022-07-20 至 2027-06-30
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10539155
关键词：
Active Biological Transport Aedes Aerosols Affect Affinity Alanine Alphavirus Alphavirus Infections Animal Model Animal Testing Antibodies Arboviruses Binding Biological Assay Biological Models Biological Products Biological Warfare Bioterrorism Birds Blood - brain barrier anatomy Brain Brain Injuries Brain region Cell Culture Techniques Cells Characteristics Charge Clinical Community Hospitals Coupled Culex (Genus)Culicidae Development Diamond Disease Eastern Equine Encephalitis Virus Engineering Epitope Mapping Epitopes Equus caballus Escape Mutant FDA approved Family Frequencies Future Genes Goals Human Imaging Techniques Immune response Immunity Immunoglobulin G Immunologics In Vitro Infection Knowledge Laser Scanning Confocal Microscopy Measurement Measures Mediating Membrane Fusion Molecular Molecular Genetics Monoclonal Antibodies Monoclonal Antibody Therapy Morbidity - disease rate Mutagenesis Mutation Nature Neuraxis Neurologic Pathogenesis Pathogenicity Prevention therapy Property Prophylactic treatment Proteomics Receptor Cell Reporting Research Research Personnel Resistance Resolution Role Route Scanning Scientist Secondary to Site Somatic Mutation Specificity Structure Survivors Testing Therapeutic Therapeutic Effect Therapeutic Monoclonal Antibodies Therapeutic Uses Togaviridae Translating Treatment Efficacy United States Vaccine Design Vaccines Variant Viral Virus Virus Diseases Work antibody engineering antigen binding base blood-brain barrier crossing climate change effective therapy env Gene Products enzootic experience experimental study human monoclonal antibodies in vivo in vivo imaging inhibiting antibody innovation insight medical countermeasure mortality mosquito-borne neutralizing antibody neutralizing monoclonal antibodies new technology next generation sequencing novel pathogen prevent prophylactic rational design receptor rural setting synergism vector viral fitness viral resistance

项目摘要

SUMMARY: Eastern equine encephalitis virus (EEEV) is a re-emerging mosquito-borne alphavirus that causes a debilitating encephalitic illness in humans. About a third of human cases of EEEV infection die and many survivors have long-term, debilitating neurologic problems. The virus is maintained in an enzootic cycle between Culiseta melanura mosquitoes and avian hosts but can be transmitted to humans and horses by some Aedes, Coquillettidia, and Culex species. The infection is unusual in humans but increasing in frequency in recent years, likely secondary to climate changes, vector expansion, and other uncharacterized factors. EEEV also is regarded as a potential bioterrorism threat due to spread via aerosol route. Despite the highly pathogenic nature of the virus, no specific treatment or vaccine for EEEV is available. A primary goal of this project is to define the molecular, genetic, immunologic, and structural characteristics of ultra-potent neutralizing human mAbs with broad activity in vivo against EEEV. Additional goals include defining the mechanistic correlates of protection by these ultra-potent neutralizing mAbs and determining ways to optimize function and deliver to the brain. In these studies, we will elucidate how antiviral Abs with exceptional inhibitory activity exert their action in cell culture and in vivo. The approach will include high efficiency isolation of human mAbs, coupled with innovative antibody gene repertoire studies based on next-gen sequencing. Several hypotheses will be tested, including the concept that ultra-potent neutralizing activity results from features of both the antibodies (selection of optimal V-D-J clonotypes and accumulation of critical somatic mutations) and the antigen (binding to quaternary epitopes on multiple adjacent envelope proteins and blockade of structural transitions critical for virus entry or release). We also will apply new technologies for receptor-mediated transfer of molecules across the blood-brain barrier using engineered sequence changes in the Fc region. Although our focus is to understand how and why ultra-potent human mAbs inhibit EEEV, the studies likely will be relevant to general principles of antibody neutralization of many different encephalitic viruses. In addition to defining the molecular and structural basis of Ab neutralization of EEEV and deploying new strategies for delivery of biologics to the brain, these studies will generate a group of fully human mAbs that can prevent and treat EEEV infection, which could be developed in the near future as a possible therapeutic for humans. Studies in this project, while targeted against EEEV, likely will inform future Ab-based and/or vaccine efforts against other arboviruses that cause human brain infections. We have assembled a unique group of investigators, including a human Ab expert, a molecular virologist with experience in Ab-virus interactions, an animal model and pathogenesis expert with specific expertise in encephalitic alphaviruses, including EEEV, and brain-targeting scientists to pursue these studies.

概括：东马脑炎病毒（EEEV）是一种重新出现的蚊子 - 传播α病毒，导致令人衰弱人类的脑病。大约三分之一的人类EEEV感染病例死亡，许多幸存者有长期，令人衰弱的神经系统问题。该病毒保持在Culiseta之间的enzootic循环中 Melanura蚊子和鸟类的寄主，但可以通过一些伊蚊，coquillettidia和culex物种。感染在人类中是不寻常的，但频率增加近年来，可能继发于气候变化，媒介扩展和其他未表征的因素。 EEEV 还被认为是通过气溶胶途径扩散的潜在生物恐怖主义威胁。尽管有高度致病性病毒的性质，没有特定治疗或疫苗的EEEV可用。这个项目的主要目标是定义超级中和人的分子，遗传，免疫和结构特征对EEEV的体内活性广泛的mAb。其他目标包括定义机械相关性通过这些超功能中和的mab保护，并确定优化功能并交付到脑。在这些研究中，我们将阐明抗病毒ABS具有特殊抑制活性在细胞培养和体内。该方法将包括高效率隔离人mab，并与基于下一代测序的创新抗体基因曲目研究。将测试几个假设，包括以下概念：两种抗体的特征超级中和活性产生最佳的V-D-J克隆型和临界体突变的积累）和抗原（结合到在多个相邻的包膜蛋白上的第四纪表位和对病毒至关重要的结构过渡的阻滞输入或发布）。我们还将将新技术应用于受体介导的分子转移使用工程序列的血脑屏障在FC区域发生变化。尽管我们的重点是了解超功能的人mab抑制EEEV，这些研究可能与许多不同不同脑病病毒的抗体中和。除了定义分子和结构对EEEV进行中和的基础，并采用新的策略将生物制剂传递给大脑，这些研究将产生一组完全可以预防和治疗EEEV感染的完全人类单元单元，这可能是在不久的将来开发，是对人类的可能治疗方法。该项目的研究，而针对 EEEV，很可能会针对引起人脑的其他arbovirus诉讼将来基于AB和/或疫苗感染。我们组装了一个独特的研究人员，包括人类AB专家，一个分子病毒学家具有AB-VIRUS相互作用的经验，动物模型和发病机理专家包括EEEV在内的脑甲状化病毒的专业知识以及促进脑力的科学家进行这些研究的专业知识。